Drug abuse, addiction, and dependence remain major threats to public health. The 2005 National Survey on Drug Use and Health reports cocaine use in 2005 was similar to that in the previous three years. Recently, methamphetamine abuse became America's number one drug threat. At present, there are no FDA approvedmedications to treat cocaine or methamphetamine abuse. Development of new pharmacotherapies to treat cocaine, methamphetamine, and other stimulant addiction would be a major medical and societal breakthrough. This application is for continuation of support for our research directed toward the design and development of potential pharmacotherapies for treating stimulant abuse. Previous studies were highly successful. 3Beta-(4-Chlorophenyl-2Beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (RTI-336) was designed and developed as an indirect dopamine agonist pharmacotherapy for cocaine addiction. Phase 1 clinical studies are planned for 2007. This research also led to other potential pharmacotherapies for cocaine addiction that warrant development. A novel strategy for treating methamphetamine and similar compounds of addiction developed in collaboration with Dr. Michael Owens (University of Arkansas) is the use of monoclonal antibodies, which will bind the drugs of abuse and alter their pharmacokinetic properties in a manner that reduces or eliminates drug use. L-Glutamic acid (glutamate) is the major excitatory neurotransmitter in the central nervous system. Several studies reported over the last few years suggest that metabotropic glutamate 5 (mGluR5) receptors play an important role in regulating the reinforcing actions of drugs of abuse. Importantly, the studies suggest that mGluR5 antagonists have potential as novel pharmacotherapies to treat addiction to cocaine and other drugs of abuse. The MERIT Award provided freedom to broaden the scope of my stimulant abuse research. This opportunity was used to initiate projects in the (1) development of monoclonal antibodies for use in treating methamphetamine abuse and (2) development of mGluR5 antagonists as potential pharmacotherapies to treat stimulant addiction. The specific aims of this competing continuation/renewal application are: (1) To design, synthesize, and couple methamphetamine haptens to appropriate proteins (BSA, OVA, others) for use in developing monoclonal antibodies as pharmacotherapies to treat methamphetamine and other stimulant addictions. (2) To design, synthesize, and develop novel mGluR5 antagonists as potential pharmacotherapies to treat cocaine and other drug addiction. (3) To continue on a limited basis our development of selected 3-phenyltropane analogs as second-generation pharmacotherapies to treat cocaine addiction.